This invention relates to novel aminopyrazole derivatives or salts thereof. More particularly, it relates to substituted pyrazole compounds represented by the following formula, or salts thereof. 
wherein:
R1 represents a group of any one of the following formulae i) to viii):
i) xe2x80x94CH(OH)xe2x80x94CH(R4)xe2x80x94(A)nxe2x80x94Y
ii) xe2x80x94CHxe2x95x90C(R4)xe2x80x94(A)nxe2x80x94Y
iii) xe2x80x94CH2xe2x80x94CH(R4)xe2x80x94(A)nxe2x80x94Y
iv) xe2x80x94COxe2x80x94B1xe2x80x94Axe2x80x94Y
v) xe2x80x94Axe2x80x94B2xe2x80x94CH(R4)xe2x80x94Y
vi) xe2x80x94Axe2x80x94CH(R4)xe2x80x94B2xe2x80x94Y
vii) xe2x80x94CH(OH)xe2x80x94CHxe2x95x90C(R4)xe2x80x94Y 
in which A is a lower alkylene group, Y is an aryl group (this aryl group may optionally be substituted by halogen, lower alkyl, lower alkoxy, amino or nitro), a cycloalkyl group or a heteroaryl group, R4 is a hydrogen atom or a lower alkyl group, B1 is xe2x80x94CH(R4)xe2x80x94 or xe2x80x94N(R4)xe2x80x94, B2 is xe2x80x94CH(OH)xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94Oxe2x80x94, and n is 0 or 1;
R2 represents a hydrogen atom, a lower alkyl group [this lower alkyl group may optionally be substituted by hydroxyl, amino, or mono- or di-(lower alkyl)amino] or an aralkyl group;
R3 represents a phenyl group (this phenyl group may optionally be substituted by halogen, trifluoromethyl or lower alkylenedioxy) or a pyridyl group; and
Q represents a pyridyl or quinolyl group.
TNF-xcex1, IL-1, IL-6 and COX-II are proteins which are predominantly produced by immunocompetent cells such as macrophages and neutrophilic leukocytes, and constitute important factors participating, for example, in immunoregulatory functions and inflammatory symptoms. TNF-xcex1 and the like are also known as factors participating in many biological reactions in the hematopoietic system, the endocrine system, the nervous system and the like. Accordingly, the excessive or uncontrolled production of TNF-xcex1 and the like in the living body are believed to be closely related to the onset and aggravation of diseases associated with TNF-xcex1 and the like.
On the other hand, p38MAP kinase found within various types of cells in the living body are known to activate, in particular, some types of transcription factors. Specifically, transcription factors such as NF-xcexaB, AP-1 and CREB bind to a certain DNA sequence common to TNF-xcex1, IL-1, IL-6, COX-II and the like, and thereby promote transcription. Within the cell nucleus, these transcription factors are activated by the action of p38MAP kinase, so that proteins such as TNF-xcex1 are synthesized from the transcribed mRNA. The mRNA which has gone out of the nucleus in the presence of calcium is inactivated by binding to a protein having a specific sequence, and decomposed rapidly. However, in the presence of p38MAP kinase activated by phosphorylation, the mRNA is released from the protein and thereby activated. Consequently, it is believed that the synthesis of proteins such as TNF-xcex1, IL-1, IL-6 and COX-II is also promoted along this pathway.
Accordingly, it is believed that the production of TNF-xcex1, IL-1, IL-6, COX-II and the like can be hindered by inhibiting p38MAP kinase. On the basis of this concept, there have been proposed a number of compounds which have a p38MAP kinase inhibiting effect and thereby hinder the production of TNF-xcex1, IL-1, IL-6, COX-II and the like (see, for example, Bioorganic and Medicinal Chemistry, Vol. 5, No. 1, pp. 49-64, 1997; and the Pamphlet of PCT International Publication WO93/14081).
It is expected that these TNF-xcex1 production inhibitors, IL-1 production inhibitors, IL-6 production inhibitors and COX-II production inhibitors will be effective in the treatment or prevention of TNF-xcex1-related diseases, IL-1-related diseases, IL-6-related diseases and COX-II-related diseases, such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, psoriasis, viral and bacterial infections, asthma, septic shock, IBD, Crohn""s disease, Alzheimer""s disease, diabetes, cachexia, osteoporosis, graft versus host disease, adult RDS, arteriosclerosis, gout, glomerulonephritis, congestive heart failure, ulcerative colitis, sepsis, cerebral malaria, restenosis, hepatitis, SLE, thrombosis, born resorption disease, chronic pulmonary inflammation disease, cardiac reperfusion injury, renal reperfusion injury, cancer, Reiter""s syndrome, preterm labor, eczema, allograft rejection, stroke, fever, Behcet""s disease, neuralgia, meningitis, sunburn, contact dermatitis, acute synovitis, spondylitis, muscle degeneration, angiogenesis, conjunctivitis, psoriatic arthritis, viral myocarditis, pancreatitis, glioblastoma, bleeding, joint inflammation, endotoxic shock, parasitic infections, tuberculosis, myocardial infarction, leprosy, diabetic retinopathy, IBS, transplant rejection, burns, bronchitis, ischemic heart disease, eclampsia, pneumonia, remission of swelling, low back pain, laryngopharyngitis, Kawasaki disease, myelopathy and atopic dermatitis.
Meanwhile, some types of pyrazole derivatives having a p38MAP kinase inhibiting effect have recently been proposed (see the Pamphlets of PCT International Publications WO98/52940 and WO98/52941).
The present inventors have now found that, among a series of pyrazole compounds in which the 5- and 3-position of the pyrazole ring is substituted by a phenyl or pyridyl group and the 4-position thereof is substituted by a pyridyl or quinolyl group, the compounds further having a certain substituent comprising an aryl, cycloalkyl or heteroaryl group attached to the 3- or 5-position of the pyrazole ring through the medium of a principal chain composed of at least two carbon, oxygen and/or nitrogen atoms have an excellent p38MAP kinase inhibiting effect and are hence exhibit an inhibitory effect on the production of TNF-xcex1, IL-1, IL-6, COX-II and the like.
Thus, the present invention provides substituted pyrazole compounds represented by the above formula (I), or salts thereof.
The term xe2x80x9clowerxe2x80x9d as used herein means that the group or compound modified by this term has 6 or less carbon atoms and preferably 4 or less carbon atoms.
Thus, examples of the xe2x80x9clower alkyl groupxe2x80x9d include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl, and examples of the xe2x80x9clower alkoxy groupxe2x80x9d include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and n-hexyloxy. Moreover, examples of the xe2x80x9clower alkylene groupxe2x80x9d include xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(C2H5)xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2xe2x80x94CH(C2H5)xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94(CH2)4xe2x80x94 and xe2x80x94(CH2)6xe2x80x94, and examples of the xe2x80x9clower alkylenedioxy groupxe2x80x9d include methylenedioxy, ethylenedioxy and propylenedioxy.
The xe2x80x9caryl groupxe2x80x9d is a monocyclic or polycyclic aromatic hydrocarbon group, and examples thereof include phenyl, indenyl and naphthyl. The xe2x80x9caralkyl groupxe2x80x9d is an alkyl group substituted by an aryl group as defined above and preferably an aryl-substituted lower alkyl group, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenypropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthymethyl and diphenylmethyl.
The xe2x80x9caryl group (this aryl group may optionally be substituted by halogen, lower alkyl, lower alkoxy, amino or nitro)xe2x80x9d represented by the symbol Y may preferably be an unsubstituted phenyl group; a phenyl group substituted by 1 or 2 substituents selected from halogen, lower alkyl, lower alkoxy, amino and nitro; or a phenyl group substituted by 3 to 5 halogen atoms.
Thus, these substituted aryl groups include, for example, 2-chlorophenyl, 3-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-aminophenyl, 4-aminophenyl, 2-nitrophenyl, 4-nitrophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2-chloro-4-fluorophenyl, 2,5-dimethylphenyl, 2,4-dimethoxyphenyl, 4-amino-3-methylphenyl, 3-methyl-4-nitrophenyl and 2,3,4,5,6-pentafluorophenyl.
The term xe2x80x9ccycloalkyl groupxe2x80x9d generally comprehends cycloalkyl groups having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The xe2x80x9cheteroaryl groupxe2x80x9d may be a monocyclic or polycyclic unsaturated heterocyclic group which contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms and, which includes a five- or six-membered ring. Alternatively, the heterocyclic ring may further be fused with a cyclic hydrocarbon group to form a fused ring. Among such heteroaryl groups, preferred ones are monocyclic or bicyclic unsaturated heterocyclic groups which contain 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur atoms, which include a five- or six-membered ring, and which may optionally be fused with a phenyl group. More preferred ones are monocyclic unsaturated heterocyclic groups which contain 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur atoms and comprise a five- or six-membered ring.
Thus, these xe2x80x9cheteroaryl groupsxe2x80x9d include, for example, pyrrolyl, furyl, thienyl, imidazolyl, pirazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, azepinyl, azocinyl, purinyl, naphthidinyl, pteridinyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, chromenyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenanthridinyl, acridinyl and dibenzazepinyl.
On the other hand, the term xe2x80x9chalogen atomxe2x80x9d comprehends fluorine, chlorine, bromine and iodine atoms.
The xe2x80x9clower alkyl group [this lower alkyl group may optionally be substituted by hydroxyl, amino, or mono- or di-(lower alkyl)amino] represented by the symbol R2 may be, for example, an unsubstituted lower alkyl group or a lower alkyl group substituted by one substituent selected from hydroxyl, amino, methylamino, ethylamino, dimethylamino and diethylamino. Preferred examples thereof include methyl, ethyl, isopropyl, n-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 4-aminobutyl, 2-dimethylaminoethyl, 2-diethylaminoethyl and 3-methylaminopropyl.
The xe2x80x9cphenyl group (this phenyl group may optionally be substituted by halogen, trifluoromethyl or lower alkylenedioxy)xe2x80x9d represented by the symbol R3 may be, for example, an unsubstituted phenyl group or a phenyl group substituted by 1 or 2 substituents selected from halogen, trifluoromethyl and lower alkylenedioxy. Preferred examples thereof include phenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-methylenedioxyphenyl and 3,4-ethylenedioxyphenyl.
The xe2x80x9cpyridyl group or quinolyl groupxe2x80x9d represented by the symbol Q may preferably be a 4-pyridyl or 4-quinolyl group.
One preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R1 is a group of the formula xe2x80x94CH2xe2x80x94CH(R4)xe2x80x94(A)nxe2x80x94Y.
Another preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which A is xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH)xe2x80x94 or xe2x80x94(CH2)2xe2x80x94.
Still another preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which Y is phenyl, 2-chlorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-aminophenyl, 4-aminophenyl, 2-nitrophenyl, 4-nitrophenyl, 2-chloro-4-fluorophenyl, 4-amino-3-methylphenyl, 3-methyl-4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, cyclohexyl, 1-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or 5-pyrimidinyl.
A further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R4 is hydrogen or methyl.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl or 2-dimethylaminoethyl.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which R3 is 3-chlorophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 3,4-methylenedioxyphenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
Still a further preferred class of compounds in accordance with the present invention are the compounds of formula (I) in which Q is 4-pyridyl.
Where R2 represents a hydrogen atom in the compounds of the above formula (I) in accordance with the present invention, such hydrogen atoms are usually attached to one of the two nitrogen atoms constituting the pyrazole ring, at a certain ratio depending on the reaction conditions and the like. Consequently, the position of substitution by R2 cannot be specified. Accordingly, the representation of the position of the substituent R2 as used in the chemical structural formula given herein means that xe2x80x9cwhere R2 represents a hydrogen atom, it is unknown which of the two nitrogen atoms constituting the pyrazole ring R2 is attached to.xe2x80x9d Where R2 represents a group other than a hydrogen atom, the position of substitution by R2 can be specified. Accordingly, the above-described representation means that xe2x80x9cwhere R2 represents a group other than a hydrogen atom, R2 is attached to a fixed one of the two nitrogen atoms constituting the pyrazole ring.xe2x80x9d
Thus, where R2 represents a hydrogen atom, it cannot be determined which of the 3- and 5-positions the substituents R1 and R3 are attached to. Accordingly, in the notation of compounds in the examples and elsewhere, the positions of substitution by R1 and R3 are represented by xe2x80x9c3(5)-xe2x80x9d or xe2x80x9c5(3)-xe2x80x9d.
In addition to the compounds described in the examples which will be given later, typical examples of the compounds of the above formula (I) which are provided by the present invention are as follows.
The compounds of formula (I) in which R1 is a group of formula i) include:
3(5)-(4-fluorophenyl)-5(3)-(1-hydroxy-5-phenylpentyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(1-naphthyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(4-tolyl)propyl]-4-(4-pyridyl)pyrazole,
5(3)-[3-(3-chlorophenyl)-1-hydroxypentyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-[3-(2,4-difluorophenyl)-1-hydroxypropyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-[3-(3,4-dichlorophenyl)-1-hydroxypropyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(2-methoxyphenyl)-propyl]-4-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(3-tolyl)butyl]-4-(4-pyridyl)pyrazole,
5(3)-(3-cyclohexyl-1-hydroxybutyl)-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(2-pyridyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(4-pyridyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(3-pyridyl)butyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-4-(3-pyridyl)butyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(3-thienyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(2-furyl)-1-hydroxypropyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(3-pyranyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(4-pyridazinyl)propyl]-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(1-hydroxy-4-phenylbutyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(1-hydroxy-2-methyl-3-phenylpropyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(1-hydroxy-3-phenylbutyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-[1-hydroxy-3-(3-tolyl)propyl]-1-methyl-4-(4-pyridyl)pyrazole,
5-(3-cyclohexyl-1-hydroxypropyl)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
1-ethyl-3-(4-fluorophenyl)-5-(1-hydroxy-3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(1-hydroxy-3-phenylpropyl)-1-isopropyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-(2-hydroxyethyl)-5-(1-hydroxy-3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(1-hydroxy-3-phenylpropyl)-1-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3(5)-(3-chlorophenyl)-5(3)-(1-hydroxy-3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3(5)-(3,4-difluorophenyl)-5(3)-(1-hydroxy-3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(3,4-difluorophenyl)-5-(1-hydroxy-3-phenylpropyl)-1-methyl-4-(4-pyridyl)pyrazole,
3(5)-phenyl-5(3)-(1-hydroxy-3-phenylpropyl)-4-(4-pyridyl)pyrazole, and the like.
The compounds of formula (I) in which R1 is a group of formula ii) include:
3(5)-(4-fluorophenyl)-5(3)-(2-methyl-3-phenyl-1-propenyl)-4-(4-pyridyl)pyrazole,
5(3)-[3-(3-chlorophenyl)-1-propenyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-(3-cyclohexyl-1-propenyl)-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(4-pyridyl)-1-propenyl]pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(3-pyridyl)-1-butenyl]pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[2-methyl-3-(3-pyridyl)-1-propenyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(3-thienyl)-1-propenyl]pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(5-pyrimidinyl)-1-propenyl]pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(2-methyl-3-phenyl-1-propenyl]-4-(4-pyridyl)pyrazole,
5(3)-(3-phenyl-1-propenyl)-3(5)-(2-pyridyl)-4-(4-pyridyl)pyrazole, and the like.
The compounds of formula (I) in which R1 is a group of formula iii) include:
3(5)-(4-fluorophenyl)-5(3)-(4-phenylpentyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(5-phenylpentyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(1-naphthyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(2-naphthyl)propyl]-4-(4-pyridyl)pyrazole,
5(3)-[3-(2-chloro-4-methylphenyl)propyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-[3-(3-chlorophenyl)propyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-[3-(2,5-difluorophenyl)propyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-[3-(2,6-difluorophenyl)propyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(2-methoxyphenyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(3-tolyl)-butyl]pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(3-pentafluorophenylpropyl)-4-(4-pyridyl)pyrazole,
5(3)-(3-cyclohexylpropyl)-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[4-(3-pyridyl)butyl]pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(3-thienyl)propyl]pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(2-furyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(3-pyranyl)propyl]-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(4-pyridazinyl)propyl]-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(4-phenylbutyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(3-phenylbutyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(2-methyl-3-phenylbutyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)-5-[3-(tolyl)propyl]pyrazole,
3-(4-fluorophenyl)-1-methyl-5-[3-(2-nitrophenyl)propyl]-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-[3-(4-nitrophenyl)propyl]-4-(4-pyridyl)pyrazole,
5-(3-cyclohexylpropyl)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
1-ethyl-3-(4-fluorophenyl)-5-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-isopropyl-5-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1,5-bis(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3(5)-(3-chlorophenyl)-5(3)-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
5(3)-(3-phenylpropyl)-4-(4-pyridyl)-3(5)-(3-trifluoromethylphenyl)pyrazole,
3(5)-(3,4-difluorophenyl)-5(3)-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3(5)-(3-chloro-4-fluorophenyl)-5(3)-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3(5)-(3,4-dichlorophenyl)-5(3)-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
5(3)-[3-(2-chloro-4-fluorophenyl)propyl]-3(5)-(2-pyridyl)-4-(4-pyridyl)pyrazole,
5(3)-(3-phenylpropyl)-3(5),4-di(4-pyridyl)pyrazole,
3(5)-phenyl-5(3)-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(3,4-difluorophenyl)-1-methyl-5-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(3-chloro-4-fluorophenyl)-1-methyl-5-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(3,4-dichlorophenyl)-1-methyl-5-(3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-(3-pyridyl)propyl]-4-(4-quinolyl)-pyrazole, and the like.
The compounds of formula (I) in which R1 is a group of formula iv) include:
3(5)-(4-fluorophenyl)-5(3)-(4-phenylbutyryl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(3-phenylbutyryl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(3-pyridyl)propionyl]pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[3-(3-pyrimidinyl)propionyl]pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(2-methyl-3-phenylpropionyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(2-methylbenzylaminocarbonyl)-4-(4-pyridyl)pyrazole,
5(3)-(3-chlorobenzylaminocarbonyl)-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-(4-fluorobenzylaminocarbonyl)-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(2-methoxybenzylaminocarbonyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(4-methoxybenzylaminocarbonyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-(2-pyridylmethylaminocarbonyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-(3-pyridylmethylaminocarbonyl)pyrazole,
5-benzylaminocarbonyl-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(1-phenethylaminocarbonyl)-4-(4-pyridyl)pyrazole,
5-(4-fluorobenzylaminocarbonyl)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(2-chlorobenzylaminocarbonyl)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(2-methoxybenzylaminocarbonyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)-5-(2-pyridylmethylaminocarbonyl)pyrazole,
5-benzylaminocarbonyl-1-ethyl-3-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
1-ethyl-3-(4-fluorophenyl)-4-(4-pyridyl)-5-(2-pyridylmethylaminocarbonyl)pyrazole,
5-benzylaminocarbonyl-3-(4-fluorophenyl)-1-(n-propyl)-4-(4-pyridyl)pyrazole,
5-benzylaminocarbonyl-3-(4-fluorophenyl)-1-isopropyl-4-(4-pyridyl)pyrazole,
5-benzylaminocarbonyl-3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(N-methyl-2-chlorobenzylaminocarbonyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(N-methyl-2-methoxybenzylaminocarbonyl)-4-(4-pyridyl)pyrazole,
5-(N,3-dimethyl-4-nitrobenzylaminocarbonyl)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
5-(N,3-dimethyl-4-aminobenzylaminocarbonyl)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(N-methyl-2-pyridylmethylaminocarbonyl)-4-(4-pyridyl)pyrazole,
1-ethyl-5-(N-ethyl-2-pyridylmethylaminocarbonyl)-3-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(N-methylbenzylaminocarbonyl)-1-(n-propyl)-4-(4-pyridyl)pyrazole,
5-(N-ethylbenzylaminocarbonyl)-3-(4-fluorophenyl)-1-(n-propyl)-4-(4-pyridyl)pyrazole, and the like.
The compounds of formula (I) in which R1 is a group of formula v) include:
3-(4-fluorophenyl)-5-(2-hydroxy-3-phenylpropyl)-1-methyl-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(1-phenylethyloxymethyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-(1-phenylethyloxy)ethyl]-4-(4-pyridyl)pyrazole,
5(3)-(2-chlorobenzyloxymethyl)-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5-benzyloxymethyl-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(1-phenylethyloxymethyl)-4-(4-pyridyl)pyrazole, and the like.
The compounds of formula (I) in which R1 is a group of formula vi) include:
3(5)-(4-fluorophenyl)-5(3)-(2-phenoxypropyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(3-phenoxypropyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[2-(3-tolyloxy)ethyl]pyrazole,
5(3)-[2-(3-chlorophenoxy)ethyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-[2-(3-fluorophenoxy)ethyl]-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
5(3)-(2-cyclohexyloxyethyl)-3(5)-(4-fluorophenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[2-(3-pyridyloxy)ethyl]pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[2-(4-pyridyloxy)ethyl]pyrazole,
3(5)-(4-fluorophenyl)-4-(4-pyridyl)-5(3)-[2-(5-pyrimidinyloxy)ethyl]pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(2-methyl-3-oxo-3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-(4-oxo-4-phenylbutyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[3-oxo-3-(3-pyridyl)propyl]-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-1-methyl-5-(3-oxo-3-phenylpropyl)-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(3-hydroxy-3-phenylpropyl)-1-methyl-4-(4-pyridyl)pyrazole, and the like.
The compounds of formula (I) in which R1 is a group of formula vii) include:
3(5)-(4-fluorophenyl)-5(3)-(1-hydroxy-3-phenyl-2-propenyl)-4-(4-pyridyl)pyrazole,
3(5)-(4-fluorophenyl)-5(3)-[1-hydroxy-3-(2-pyridyl)-2-propenyl]-4-(4-pyridyl)pyrazole,
3-(4-fluorophenyl)-5-(1-hydroxy-3-phenyl-2-propenyl)-1-methyl-4-(4-pyridyl)pyrazole, and the like.
The compounds of formula (I) in which R1 is a group of formula viii) include:
3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)-5-[N-(1,2,3,4-tetrahydroisoquinolinyl)carbonyl]pyrazole, and the like.
The compounds of formula (I) in accordance with the present invention can form salts. Examples of such salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and salts formed with organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid and p-toluenesulfonic acid. Among others, pharmaceutically acceptable salts are preferred.
According to the present invention, depending on the types of the substituents represented by R1 and R2, the compounds of the above formula (I) may be prepared, for example, by any of the processes (a) to (j) described below.
Process (a): The compounds of the above formula (I) in which R2 is a hydrogen atom and R1 is a group of formula i) may be prepared by:
(i) reacting an amino compound of the formula 
wherein R3 and Q have the above-defined meanings, with an aldehyde compound of the formula
HOCxe2x80x94CH(R4)xe2x80x94(A)nxe2x80x94Yxe2x80x83xe2x80x83(III)
wherein R4, A, n and Y have the above-defined meanings.
Process (b): The compounds of the above formula (I) in which R2 is a hydrogen atom and R1 is a group of formula ii) may be prepared by subjecting a compound of formula (I) in which R1 is a group of formula i), to a dehydration reaction.
Process c): The compounds of the above formula (I) in which R2 is a hydrogen atom and R1 is a group of formula iii) may be prepared by:
(c-1) subjecting a compound of formula (I) in which R1 is a group of formula ii), to a reduction reaction; or
(c-2) reacting an ethanone compound of the formula 
wherein R3 and Q have the above-defined meanings, with an imide ester compound of the formula
Suxe2x80x94Oxe2x80x94COxe2x80x94CH2xe2x80x94CH(R4)xe2x80x94(A)nxe2x80x94Yxe2x80x83xe2x80x83(V)
wherein Su represents a succinimide group, and R4, A, n and Y have the above-defined meanings, and reacting the resulting compound of the formula 
wherein R3, R4, A, n, Y and Q have the above-defined meanings, with hydrazine or a hydrate thereof.
Process (d): The compounds of the above formula (I) in which R2 is a hydrogen atom, R1 is a group of formula iv), and B1 is xe2x80x94CH(R4)xe2x80x94 may be prepared by subjecting a compound of formula (I) in which R1 is a group of formula i) and n is 1, to an oxidation reaction.
Process (e): The compounds of the above formula (I) in which R2 is a hydrogen atom, R1 is a group of formula iv), and B1 is xe2x80x94CH(R4)xe2x80x94 may be prepared by reacting a carboxy compound of the formula 
wherein R2, R3 and Q have the above-defined meanings, with an amino compound of the formula
NH(R4)xe2x80x94Axe2x80x94Yxe2x80x83xe2x80x83(VIII)
wherein R4, A and Y have the above-defined meanings.
Process f): The compounds of the above formula (I) in which R2 is a hydrogen atom and R1 is a group of formula v) may be prepared by reacting an ethanone compound of formula (IV) with an imide ester compound of the formula
Suxe2x80x94Oxe2x80x94COxe2x80x94Axe2x80x94B21xe2x80x94CH(R4)xe2x80x94Yxe2x80x83xe2x80x83(IX)
wherein B21 is a protected hydroxymethylene group, a protected carbonyl group or xe2x80x94Oxe2x80x94, and Su, R4, A and Y have the above-defined meanings; reacting the resulting compound of the formula 
wherein R3, R4, A, B21, Y and Q have the above-defined meanings, with hydrazine or a hydrate thereof; when B21 in the resulting compound represents a protected hydroxymethylene group or a protected carbonyl group, eliminating the protecting group as required; and, when B1 in the resulting compound represents xe2x80x94COxe2x80x94, reducing the compound as required.
Process (g): The compounds of the above formula (I) in which R2 is a hydrogen atom and R1 is a group of formula vi) may be prepared by reacting a compound of the above formula (II) with a bromo compound of the formula
Brxe2x80x94Axe2x80x94CH(R4)xe2x80x94B2xe2x80x94Yxe2x80x83xe2x80x83(XI)
wherein A, R4, B2 and Y have the above-defined meanings.
Process (h): The compounds of the above formula (I) in which R2 is a hydrogen atom and R1 is a group of formula vii) may be prepared by reacting a compound of the above formula (II) with an aldehyde compound of the formula
HOCxe2x80x94CHxe2x95x90C(R4)xe2x80x94Yxe2x80x83xe2x80x83(XII)
wherein R4 and Y have the above-defined meanings.
Process (i): The compounds of the above formula (I) in which R2 is a hydrogen atom and R1 is a group of formula viii) may be prepared by reacting a carboxy compound of formula (VII) with 1,2,3,4-tetrahydroisoquinoline.
Process (j): The compounds of the above formula (I) in which R2 is an optionally substituted lower alkyl group or an aralkyl group may be prepared by treating a compound of formula (I) in which R2 is a hydrogen atom, with a lower alkyl halide or an aralkyl halide.
In the above-described process (a), the reaction of a compound of formula (II) with an aldehyde compound of formula (III) may generally be carried out in an inert organic solvent selected, for example, from ethers such as tetrahydrofuran, dioxane and dimethoxyethane; and aromatic hydrocarbons such as benzene and toluene. Usually, the compound of formula (II) is first treated with a strong base such as n-butyl lithium, tert-butyl lithium, potassium tert-butoxide, lithium diisopropylamide or lithium bis(trimethylsilyl)amide, and then reacted with the aldehyde compound of formula (III). As to the reaction temperature, it is usually preferable to carry out the treatment with the strong base at a temperature of about xe2x88x9265xc2x0 C. or below, and it is usually suitable to carry out the subsequent reaction with the aldehyde compound of formula (III) at a temperature ranging from an ice-cold temperature to room temperature.
The proportion of the aldehyde compound of formula (III) to the compound of formula (II) may generally be such that the aldehyde compound of formula (III) is used in an amount of at least 1 mole, preferably 1 to 2 moles, and more preferably 1.05 to 1.5 moles, per mole of the compound of formula (II). The strong base may generally be used in an amount of at least 1 mole, preferably 1 to 2 moles, and more preferably 1.05 to 1.5 moles, per mole of the compound of formula (II).
In the above-described process (b), the dehydration reaction of a compound of formula (I) in which R1 is a group of formula i), namely a compound of the following formula (I-1) 
wherein R2, R3, R4, A, n, Y and Q have the above-defined meanings, may generally be carried out in an inert organic solvent selected, for example, from aromatic hydrocarbons such as benzene, toluene and xylene; and sulfoxides such as dimethyl sulfoxide, optionally with the aid of a dehydrating agent such as 4-toluenesulfonic acid or camphorsulfonic acid. As the reaction temperature, it is usually suitable to employ a temperature ranging from room temperature to the reflux temperature of the reaction mixture and preferably from about 50xc2x0 C. to the reflux temperature of the reaction mixture.
When a dehydrating agent is used in the dehydration reaction, the proportion of the dehydration agent to the compound of formula (I-1) may generally be such that the dehydrating agent is used in an amount of at least 1 mole, preferably 1.1 to 5 moles, and more preferably 1.5 to 3 moles, per mole of the compound of formula (I-1).
In the above-described process (c-1), the reduction reaction of a compound of formula (I) in which R1 is a group of formula ii), namely a compound of the following formula (I-2) 
wherein R2, R3, R4, A, n, Y and Q have the above-defined meanings, may generally be carried out by hydrogenating the compound at atmospheric pressure or elevated pressure in a solvent selected, for example, from alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran, dioxane and dimethoxyethane; and esters such as ethyl acetate, and in the presence of a catalyst such a palladium-carbon, hydrogenated palladium-carbon or Raney nickel. As the reaction temperature, it is usually suitable to employ a temperature in the range of 0xc2x0 C. to 60xc2x0 C. and preferably in the vicinity of room temperature.
In the above-described process (c-2), the reaction of an ethanone compound of formula (IV) with an imide ester compound of formula (V) may generally be carried out in an inert organic solvent selected, for example, from ethers such as tetrahydrofuran, dioxane and dimethoxyethane; and aromatic hydrocarbons such as benzene and toluene. Specifically, the ethanone compound of formula (IV) is first treated with a strong base such as sodium tert-butoxide, potassium tert-butoxide, tert-butyl lithium, n-butyl lithium, lithium diisopropylamide or lithium bis(trimethylsilyl)amide, and then reacted with the imide ester compound of formula (V). As to the reaction temperature, it is usually preferable to carry out the treatment with the strong base at a temperature of about xe2x88x9265xc2x0 C. or below, and it is usually suitable to carry out the subsequent reaction with the imide ester compound of formula (V) at a temperature ranging from an ice-cold temperature to room temperature.
The proportion of the imide ester compound of formula (V) to the ethanone compound of formula (IV) may generally be such that the imide ester compound of formula (V) is used in an amount of at least 1 mole, preferably 1 to 5 moles, and more preferably 1.5 to 2.0 moles, per mole of the ethanone compound of formula (IV).
The resulting compound of formula (VI) may subsequently be reacted with hydrazine or a hydrate thereof and thereby converted to a compound of formula (I) which is desired in the present invention, namely a compound of formula (I) in which R2 is a hydrogen atom and R1 is a group of formula iii).
The reaction of the compound of formula (VI) with hydrazine or a hydrate thereof may generally be carried out in an inert solvent selected, for example, from water; ethers such as tetrahydrofuran, dioxane and diethyl ether; and alcohols such as methanol, ethanol and propanol. As the reaction temperature, it is usually suitable to employ a temperature ranging from an ice-cold temperature to about 50xc2x0 C. and preferably in the vicinity of room temperature.
In the above-described process (d), the oxidation reaction of a compound of formula (I) in which R1 is a group of formula i) and n is 1, namely a compound of the following formula (I-1-1) 
wherein R2, R3, R4, A, Y and Q have the above-defined meanings, may generally be carried out by treating the compound with an oxidizing agent such as a combination of 2,2,6,6-tetramethyl-1-piperidyloxy radical and sodium hypochlorite; a combination of oxalyl chloride, dimethyl sulfoxide and trimethylamine; pyridinium chlorochromate; or pyridinium dichromate, in an inert organic solvent selected, for example, from halogenated hydrocarbons such as dichloromethane and chloroform. As the reaction temperature, it is usually suitable to employ a temperature ranging approximately from xe2x88x9220xc2x0 C. to room temperature and preferably from xe2x88x9210xc2x0 C. to an ice-cold temperature.
In this oxidation reaction, the proportion of the oxidizing agent to the compound of formula (I-1-1) may generally be such that the oxidizing agent is used in an amount of at least 1 mole, preferably 1 to 6 moles, and more preferably 1 to 2 moles, per mole of the compound of formula (I-1-1).
In the above-described process (e), the reaction of a carboxy compound of formula (VII) with an amino compound of formula (VIII) may generally be carried out in an inert organic solvent selected, for example, from amides such as dimethylformamide and dimethylacetamide; and halogenated hydrocarbons such as dichloromethane and chloroform. Specifically, this can be done by first converting the carboxy compound of formula (VII) to its reactive derivative (e.g., its N-hydroxysuccinimide ester, pentafluorophenyl ester, or p-nitrophenyl ester) and then reacting this derivative with the amino compound of formula (VIII); or by reacting the carboxy compound of formula (VII) with the amino compound of formula (VIII) in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC), diethyl cyanophosphate (DEPC) or diphenylphosphoryl azide (DPPA). As the reaction temperature, it is usually suitable to employ a temperature ranging from an ice-cold temperature to room temperature.
The proportion of the amino compound of formula (VIII) to the carboxy compound of formula (VII) may generally be such that the amino compound of formula (VIII) is used in an amount of at least 1 mole, preferably 1 to 2 moles, and more preferably 1 to 1.5 moles, per mole of the carboxy compound of formula (VII).
In the above-described process (f), the reaction of an ethanone compound of formula (IV) with an imide ester compound of formula (IX), and the subsequent reaction with hydrazine or a hydrate thereof may be carried out in the same manner as described above in connection with the process (c-2). When B21 in the resulting compound represents a protected hydroxymethylene group or a protected carbonyl group, the protecting group may be eliminated in the usual manner, for example, by using a hydrolysis reaction, a catalytic hydrogenolysis reaction or the like according to the type of the protecting group.
When B2 in the resulting compound represents xe2x80x94COxe2x80x94, the compound may be reduced, for example, with the aid of a complex metal hydride such as lithium aluminum hydride.
In the above-described process (g), the reaction of a compound of formula (II) with a bromo compound of formula (XI) may generally be carried out in an inert organic solvent selected, for example, from ethers such as tetrahydrofuran, dioxane and dimethoxyethane; and aromatic hydrocarbons such as benzene and toluene. Usually, the compound of formula (II) is first treated with a strong base such as n-butyl lithium, tert-butyl lithium, potassium tert-butoxide, lithium diisopropylamide or lithium bis(trimethylsilyl)amide, and then reacted with the bromo compound of formula (XI). As to the reaction temperature, it is usually preferable to carry out the treatment with the strong base at a temperature of about xe2x88x9265xc2x0 C. or below, and it is usually suitable to carry out the subsequent reaction with the bromo compound of formula (XI) at a temperature ranging from an ice-cold temperature to room temperature.
The proportion of the bromo compound of formula (XI) to the compound of formula (II) may generally be such that the bromo compound of formula (XI) is used in an amount of at least 1 mole, preferably 1 to 2 moles, and more preferably 1 to 1.5 moles, per mole of the compound of formula (II). The strong base may generally be used in an amount of at least 1 mole, preferably 1 to 2 moles, and more preferably 1 to 1.5 moles, per mole of the compound of formula (II).
In the above-described process (h), the reaction of a compound of formula (II) with an aldehyde compound of formula (XII) may be carried out in the same manner as described above in connection with the process (a).
In the above-described process (i), the reaction of a carboxy compound of formula (VII) with 1,2,3,4-tetrahydroisoquinoline may be carried out in the same manner as described above in connection with the process (e).
In the above-described process (j), the treatment of a compound of formula (I) in which R2 is a hydrogen atom, with a lower alkyl halide or an aralkyl halide may generally be carried out in an inert organic solvent selected, for example, from ethers such as dioxane, tetrahydrofuran and dimethoxyethane; amides such as dimethylformamide and dimethylacetamide; and aromatic hydrocarbons such as benzene and toluene, and with the aid of a base such as sodium hydride, sodium amide or potassium t-butoxide. The lower alkyl halides which can be used in this treatment include, for example, methyl iodide, ethyl iodide and isopropyl iodide. The aralkyl halide which can be used include, for example, benzyl iodide and phenethyl iodide. As the reaction temperature, it is usually suitable to employ a temperature ranging from about 0xc2x0 C. to the reflux temperature of the reaction mixture and preferably from an ice-cold temperature to room temperature.
The proportion of the lower alkyl halide or aralkyl halide to the compound of formula (I) in which R2 is a hydrogen atom may generally be such that the lower alkyl halide or aralkyl halide is used in an amount of at least 1 mole, preferably 1.05 to 2 moles, and more preferably 1.1 to 1.5 moles, per mole of the compound of formula (I).
In this reaction, when lower alkyl group represented by R2 is substituted by hydroxyl or amino, it is advantageous to protect this substituent group suitably with an appropriate protecting group (e.g., cyclic imide, dibenzyl, benzyloxycarbonyl or t-butoxycarbonyl for amino; and benzyl, acetyl or methoxymethyl for hydroxyl) in advance and eliminate the protecting group after completion of the reaction.
Thus, the substituted pyrazole compounds of the above formula (I) which are desired in the present invention can be formed.
The compounds of the above formula (I) or their salts, which have been formed in the above-described manner, may be isolated and purified from the reaction mixture by per se known techniques such as recrystallization, distillation, column chromatography and thin-layer chromatography.
The compounds of the above formula (II), which are used as starting materials in the above-described reactions, are novel compounds which have not been described in the literature of the prior art. They may readily be prepared, for example, by treating a compound of the following formula (XIII) with formaldehyde and pyrrolidine. 
wherein R3 and Q have the above-defined meanings. For the details of the reaction conditions, reference should be made to Synthesis Example 1 which will be given later.
The substituted pyrazole compounds of formula (I) or their salts in accordance with the present invention, which have been described above, have an excellent p38MAP kinase inhibiting effect and are hence exhibit an inhibitory effect on the production of TNF-xcex1, IL-1, IL-6, COX-II and the like. Accordingly, they are useful as agents for the treatment of TNF-xcex1-related diseases, IL-1-related diseases, IL-6-related diseases and COX-II-related diseases, such as rheumatoid arthritis, multiple sclerosis, osteoarthritis, psoriasis, HIV, asthma, septic shock, IBD, Crohn""s disease, Alzheimer""s disease, diabetes, cachexia, osteoporosis, graft versus host disease, adult RDS, arteriosclerosis, gout, glomerulonephritis, congestive heart failure, ulcerative colitis, sepsis, cerebral malaria, restenosis, hepatitis, SLE, thrombosis, born resorption disease, chronic pulmonary inflammation disease, cardiac reperfusion injury, renal reperfusion injury, cancer, Reiter""s syndrome, preterm labor, eczema, allograft rejection, stroke, fever, Behcet""s disease, neuralgia, meningitis, sunburn, contact dermatitis, acute synovitis, spondylitis, muscle degeneration, angiogenesis, conjunctivitis, psoriatic arthritis, viral myocarditis, pancreatitis, glioblastoma, bleeding, joint inflammation, endotoxic shock, parasitic infections, tuberculosis, myocardial infarction, leprosy, diabetic retinopathy, IBS, transplant rejection, burns, bronchitis, ischemic heart disease, eclampsia, pneumonia, remission of swelling, low back pain, laryngopharyngitis, Kawasaki disease, myelopathy and atopic dermatitis.
The p38MAP kinase inhibiting effects of the compounds of formula (I) or their salts in accordance with the present invention can be measured in the following manner.
(1) Measurement of inhibitory activities against the binding of p38MAP kinase
Inhibitory activities against the binding of p38MAP kinase were measured by use of the cytosol fraction of THP-1 cells which are cultured cells derived from human monocytes. Specifically, THP-1 cells were suspended in a cell lysis buffer [20 mM Tris-HCl buffer (pH 7.4), 1 mM magnesium chloride, 1 mM PMSF (phenylmethylsulfonyl fluoride), 1 mM pepstatin A, 1 mM leupeptin, 10 mg/ml aprotinin] and then ultrasonicated in water. Thereafter, the suspension was centrifuged at 100,000xc3x97g for 1 hour, and the protein concentration of the resulting supernatant (cytosol fraction) was determined. This supernatant was diluted with the cell lysis buffer so that the protein concentration of the cytosol fraction was 1 mg/ml, dispensed, and stored at xe2x88x9280xc2x0 C. till use.
The inhibitory activity of a test compound against the binding of p38MAP kinase was measured by incubating a mixture of the cytosol fraction (100 xcexcg protein) of THP-1 cells and the test compound at 15xc2x0 C. for 30 minutes, adding thereto 1.11 KBq of 3H-SB202190 (925 GBq/mmol; manufactured by Amersham, England) as a radioligand, and reacting the resulting mixture at 15xc2x0 C. for 3 hours. Nonspecific binding was measured by adding 20 xcexcM SB203580. In order to separate the free and bound types of radioligand, a charcoal solution (1% charcoal, 0.1% dextran T-70). The resulting mixture was cooled with ice for 15 minutes and then centrifuged (3,000 rpm, 10 minutes, 4xc2x0 C.). After the addition of a liquid scintillator to the resulting supernatant, its radioactivity was measured with a liquid scintillation counter.
3H-SB202190 used as a radioligand was 4-(4-fluorophenyl)-2-(4-hydroxy-3,5-di-3H-phenyl)-5-(4-pyridyl)imidazole, and SB203580 added for the measurement of nonspecific binding was 4-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-5-(4-pyridyl)imidazole.
The results of measurement of compounds in accordance with the present invention are given below.
As described above, the compounds of the above formula (I) or salts thereof in accordance with the present invention have an excellent inhibitory activity against the binding of p38MAP kinase, and can hence be used as p38MAP kinase inhibitors for purposes of prophylaxis, therapy and treatment in human beings and other mammals by oral administration or parenteral administration (e.g., intramuscular injection, intravenous injection, intra-articular administration, intrarectal administration or percutaneous administration).
When the compounds of the present invention are used as drugs, they may be formed into any of various pharmaceutical preparations according to the intended purpose. These pharmaceutical preparations include solid preparations (e.g., tablets, hard capsules, soft capsules, granules, powders, fine subtilaes, pills, troches and patches), semisolid preparations (e.g., suppositories and ointments), and liquid preparations (e.g., injections, emulsions, suspensions, lotions and sprays). Nontoxic additives which can be used in the aforesaid pharmaceutical preparations include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose and salts thereof, acacia, polyethylene glycol, alkyl esters of p-hydroxybenzoic acid, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate and citric acid. The aforesaid pharmaceutical preparations may also contain other therapeutically useful drugs.
The content of the compounds of the present invention in the aforesaid pharmaceutical preparations may vary according to the dosage form. Generally, it is desirable that solid and semisolid preparations contain the compounds of the present invention at a concentration of 0.1 to 50% by weight and liquid preparations contain them at a concentration of 0.05 to 10% by weight.
The dosage of the compounds of the present invention may vary widely according to the type and body weight of the mammal (including human being) to be treated, the route of administration, the severity of symptoms, the doctor""s diagnosis, and the like. Generally, they may be administered in a daily dose of 0.02 to 10 mg/kg and preferably 0.1 to 2 mg/kg. However, it is a matter of course that they may be administered in doses less than the lower limit of the aforesaid range or greater than the upper limit thereof, depending on the severity of symptoms in the patient and the doctor""s diagnosis. The aforesaid daily dose may be given at a time or in several divided doses.